The α-helix, the most prevalent type of secondary structure found in proteins, forms the cornerstone of the three-dimensional architecture of proteins and regulates numerous biological activities. Water-soluble peptides that adopt stable α-helix conformations are attractive motifs because of their importance in basic science and their broad utility in medicine. As a motif with a unique folding/unfolding property and a rigid, rod-like morphology, the α-helix has been the subject of intense study and has been broadly used as a building block in the design of therapeutics and molecular assemblies (see for example, Zhang, Nat. Biotechnol. 21, 1171-1178 (2003); Hartgerink et al., Science 294, 1684-1688 (2001); and Nowak et al., Nature 417, 424-428 (2002)).
Polypeptides bearing an α-helical conformation can be made entirely of hydrophobic amino acids such as alanine and leucine because such polypeptides have high helical propensities due to the hydrophobic amino acids (Chakrabartty et al., Protein Sci. 3, 843-852 (1994); Levy et al., Proc. Natl. Acad. Sci. U.S.A. 98, 2188-2193 (2001); Dobson et al., Angew. Chem., Int. Ed. 37, 868-893 (1998)). However, the usefulness of these structures is limited because of their poor aqueous solubility and processability.
Incorporating charged amino acid residues to improve peptide solubility, however, usually leads to reduced helical stability due to increased side-chain charge repulsion and the disruption of intra-molecular hydrogen bonding. Access to stable, water-soluble α-helical polypeptides would facilitate peptide research and provide useful tools for developing new peptide applications.